The use of regulatory or immature dendritic cells (DCs) as tools for modulating experimental rheumatoid arthritis is very recent. TNF-stimulated DCs have been shown to restore tolerance in experimental autoimmune encephalomyelitis and collagen-induced arthritis (CIA).
Objective: We investigated the capacity of short-term lipopolysaccharide (LPS)-stimulated DCs pulsed with type-II collagen (CII) to induce tolerance against established CIA.
Methods: Bone marrow-derived DCs were generated in the presence of GM-CSF. After CIA induction, mice were injected at day 35 with a single dose of 4- or 24-hour LPS-stimulated DCs that had been loaded with CII (CII/DCs, 4hLPS/CII/DCs or 24hLPS/CII/DCs). Arthritis progression was monitored by clinical and histologic evaluations.
Results Flow cytometry of 4hLPS/CII/DCs showed intermediate CD40 and CD86 expression, lower than that of 24hLPS/CII/DCs (fully mature) and higher than that of CII/DCs (immature). A functional assay showed that 4hLPS/CII/DCs display increased endocytosis ability with respect to 24hLPS/CII/DCs, indicating a semi-mature state. The single inoculation of 4hLPS/CII/DCs in mice with established CIA reduced significantly disease severity over time. Histologic evaluation of mice treated with 4hLPS/CII/DCs revealed diminished inflammatory synovitis, cartilage damage and fibrosis. Co-cultures of DCs with splenocytes from CIA mice showed that collagen-specific IFNγ production was dramatically inhibited by 4hLPS/CII/DCs. 4hLPS/CII/DCs were high IL-10 producers which could explain the inhibition of arthritis progression in mice receiving this treatment because neither antibodies nor regulatory CD4+CD25+Foxp3+ T lymphocytes were demonstrated to be involved.
Conclusion: Short-term LPS-modulated DCs inoculation interferes with CIA progression when loaded with CII.
- dendritic cells
- regulatory cells
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